The overall objectives of these studies are the understanding of the pathogenesis of Huntington's disease and the mechanism underlying maternal inheritance of the Westphal variant, with a view toward improving diagnosis and treatment. Our immediate objective is to test the hypothesis that Huntington's disease is associated with a defect of mitochondrial oxidative phosphorylation, as has been suggested by previous clinical, genetic, and biochemical studies of this disorder. Our specific aims are to: (1) Compare oxidative phosphorylation in Huntington's and control brain specimens, using polarography, spectrophotometry, and enzymatic analysis of previously frozen tissue; (2) to determine if the ratio of glucose to oxygen uptake in the caudates of affected individuals reflects impaired utilization of oxidative phosphorylation, (3) to investigate possible interactions between the autosomal Huntington's gene and the mitochondrial genome by searching for gross structural abnormalities of mitochondrial DNA in Huntington's brains, comparison of the relative ploidy of mitochondrial and nuclear genomes in Huntington's and control brains, and by comparison of the sequence of mitochondrial DNA in individuals who have wither early or late onset of the disease. Verification of impaired oxidative phosphorylation and demonstration of interactions of the Huntington's gene and the mitochondrial genome would improve our understanding of pathogenesis, provide useful constraints for the identification of the Huntington's gene, and may provide the basis for rationale therapy of this disorder.